|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 277, Issue 31, 28330-28339, August 2, 2002
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the Department of Pathology and Laboratory Medicine,
University of Pennsylvania School of Medicine and the Abramson
Family Cancer Research Institute, Philadelphia, Pennsylvania 19104
Members of the erbB family receptor
tyrosine kinases (erbB1, erbB2, erbB3, and erbB4) are overexpressed in
a variety of human cancers and represent important targets for the
structure-based drug design. Homo- and heterodimerization
(oligomerization) of the erbB receptors are known to be critical
events for receptor signaling. To block receptor self-associations, we
have designed a series of peptides derived from potential dimerization
surfaces in the extracellular subdomain IV of the erbB receptors (erbB peptides). In surface plasmon resonance (BIAcore) studies, the designed
peptides have been shown to selectively bind to the erbB receptor
ectodomains and isolated subdomain IV of erbB2 with submicromolar affinities and to inhibit heregulin-induced interactions of erbB3 with
different erbB receptors. A dose-dependent inhibition of native erbB receptor dimerization by the erbB peptides has been observed in 32D cell lines transfected with different combinations of
erbB receptors. The peptides effectively inhibited growth of two types
of transformed cells overexpressing different erbB receptors, T6-17 and
32D, in standard MTT
(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and cell
viability assays. The study identifies distinct loops within the
membrane-proximal part of the subdomain IV as potential
receptor-receptor interaction sites for the erbB receptors and
demonstrates the possibility of disabling receptor activity by
structure-based targeting of the dimerization interfaces. Molecular models for possible arrangement of the erbB1·EGF complex,
consistent with the involvement of subdomain IV in inter-receptor
interactions, are proposed. Small dimerization inhibitors described
herein can be useful as probes to elucidate different erbB signaling
pathways and may be developed as therapeutic agents.
Disabling Receptor Ensembles with Rationally
Designed Interface Peptidomimetics*
, and
*
This work was supported by grants from the Abramson Cancer
Institute, NCI, National Institutes of Health (to M. I. G.), and from
the American Cancer Society Institutional Research Grant (IRG-78-002-23) (to R. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence may be addressed: Dept. of Pathology and
Laboratory Medicine, University of Pennsylvania School of Medicine, 252 John Morgan Bldg., 36th and Hamilton Walk, Philadelphia, PA 19104. Tel.: 215-573-9256; Fax: 215-898-2401; E-mail:
greene@reo.med.upenn.edu.
§
To whom correspondence may be addressed: Dept. of Pathology and
Laboratory Medicine, University of Pennsylvania School of Medicine, 252 John Morgan Bldg., 36th and Hamilton Walk, Philadelphia, PA 19104. Tel.: 215-898-2847; Fax: 215-898-2401; E-mail:
murali@xray.med.upenn.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Afshar, T. Asai, and S. L. Morrison Humanized ADEPT comprised of an engineered human purine nucleoside phosphorylase and a tumor targeting peptide for treatment of cancer Mol. Cancer Ther., January 1, 2009; 8(1): 185 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Kim, D. G. Jeong, S. K. Jeong, T.-S. Yoon, and S. E. Ryu Crystal Structure of the Major Diabetes Autoantigen Insulinoma-Associated Protein 2 Reveals Distinctive Immune Epitopes Diabetes, January 1, 2007; 56(1): 41 - 48. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. Dawson, M. B. Berger, C.-C. Lin, J. Schlessinger, M. A. Lemmon, and K. M. Ferguson Epidermal Growth Factor Receptor Dimerization and Activation Require Ligand-Induced Conformational Changes in the Dimer Interface Mol. Cell. Biol., September 1, 2005; 25(17): 7734 - 7742. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. C. Peterson, M. D. Servinsky, A. Christian, Z. Peng, W. Qiu, J. Mann, J. Dicello, and D. L. Huso Tamoxifen resistance and Her2/neu expression in an aged, irradiated rat breast carcinoma model Carcinogenesis, September 1, 2005; 26(9): 1542 - 1552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kani, C. M. Warren, C. S. Kaddis, J. A. Loo, and R. Landgraf Oligomers of ERBB3 Have Two Distinct Interfaces That Differ in Their Sensitivity to Disruption by Heregulin J. Biol. Chem., March 4, 2005; 280(9): 8238 - 8247. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. K. Dakappagari, K. D. Lute, S. Rawale, J. T. Steele, S. D. Allen, G. Phillips, R. T. Reilly, and P. T. P. Kaumaya Conformational HER-2/neu B-cell Epitope Peptide Vaccine Designed to Incorporate Two Native Disulfide Bonds Enhances Tumor Cell Binding and Antitumor Activities J. Biol. Chem., January 7, 2005; 280(1): 54 - 63. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hasegawa, X. Cheng, K. Kajino, A. Berezov, K. Murata, T. Nakayama, H. Yagita, R. Murali, and M. I. Greene Fas-disabling small exocyclic peptide mimetics limit apoptosis by an unexpected mechanism PNAS, April 27, 2004; 101(17): 6599 - 6604. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kumagai, M. Katsumata, A. Hasegawa, K. Furuuchi, T. Funakoshi, I. Kawase, and M. I. Greene Role of extracellular subdomains of p185c-neu and the epidermal growth factor receptor in ligand-independent association and transactivation PNAS, August 5, 2003; 100(16): 9220 - 9225. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |